Intrauterine Progestin Therapy as a New Approach to Premalignant Endometrial Polyps: A Prospective Observational Study.

BACKGROUND/AIM: Endometrial hyperplastic polyps (EHP) may progress to endometrial carcinoma (EC) if left untreated. We aimed to prospectively investigate the efficacy of the low-dose levonorgestrel intrauterine system (LNG-IUS) as therapy for EHP with malignant potential. PATIENTS AND METHODS: In total, 37 women with EHP underwent therapy with LNG-IUS containing 13.5 mg levonorgestrel for six months or 4-10 weeks depending on whether the EHP was characterized (by D-score analysis) as low- to medium-risk (n=33) or high-risk (n=4) of coexistent or future EC. Therapy response was defined as complete clearance of hyperplastic glands in post-therapy endometrial biopsy. RESULTS: All women with low- to medium-risk EHP obtained therapy response, whereas only 1 out of 4 with high-risk EHP responded to therapy. None of the women were diagnosed with EC during the study and no serious adverse events occurred. CONCLUSION: Low-dose LNG-IUS represents a promising therapy for selected women with EHP.

Low-dose LNG-IUS as Therapy for Endometrial Hyperplasia. A Prospective Cohort Pilot Study.

BACKGROUND/AIM: Progestin therapy has been accepted as therapy for low- and medium-risk endometrial hyperplasia. The aim of this study was to investigate the efficacy of the low-dose levonorgestrel-impregnated intrauterine system (LNG-IUS) 13.5 mg (Jaydess®, Bayer Pharmaceuticals, Berlin, Germany) as therapy for endometrial hyperplasia. PATIENTS AND METHODS: A total of 21 women with histologically-verified endometrial hyperplasia were prospectively treated with LNG-IUS Jaydess. Therapy duration was 6 months (n=16) or 3-6 weeks (n=5) depending on individual risk (low- and medium-risk versus high-risk) for co-existent or future endometrial carcinoma. Paired endometrial biopsies were sampled prior to and after therapy and classified according to the WHO94 classification system and D-score. RESULTS: All women with low- and medium risk endometrial hyperplasia had-therapy response. In the group of women with high-risk endometrial hyperplasia only 40% (two out of five) obtained a therapy response. CONCLUSION: Low-dose LNG-IUS Jaydess was proven to be an excellent therapy option for low- and medium-risk endometrial hyperplasia. For patients with high-risk endometrial hyperplasia hysterectomy or LNG-IUS therapy under close surveillance is advised.

Treatment results of endometrial hyperplasia after prospective D-score classification: a follow-up study comparing effect of LNG-IUD and oral progestins versus observation only.

OBJECTIVES: Three different treatment options for endometrial hyperplasia were evaluated in a prospective long-time follow-up study, comparing effects of intrauterine levonorgestrel impregnated device (LNG-IUD), low oral dose of medroxyprogesterone acetate (MPA) and no treatment (observation only). To select patients with high probability for co-existing or future carcinoma we used the objective morphometric algorithm, D-score, stratifying patients into three different risk groups. As far as we know, this is the first prospective long-time follow-up study in which treatment recommendation and outcome is based on the D-score assessment. METHODS: From a total of 370 patients initially diagnosed with endometrial hyperplasia from eight different hospitals in North Norway, 258 were available for long-time follow-up. After D-score classification, one of three different treatment options was chosen: LNG-IUD, low oral dose of MPA or observation only. Follow-up controls were performed and biopsies taken in the local hospitals. RESULTS: Among the 370 investigated cases with endometrial hyperplasia, only ten endometrial cancers were detected at the entrance of the study, all belonging to the high risk group (D-score <0). No further cancers were detected during follow-up, irrespective of risk group. After 6 months treatment with LNG-IUD proved significantly superior to oral treatment (p=0.001 for D-score >1 and p=0.003 for D-score 0-1 groups) and observation only (p=0.001 for D-score >1 and p=0.001 for D-score 0-1 groups). After 56 to 108 months the LNG-IUD proved significantly superior to oral treatment and to the observation group. Comparison of oral therapy to observation only showed no significant differences, neither after 6 months nor after long-time observation. CONCLUSIONS: LNG-IUD is the optimal treatment for endometrial hyperplasia. Outcome after oral low-dose MPA regimen is comparable to expectation.

Effect of levonorgestrel IUD and oral medroxyprogesterone acetate on glandular and stromal progesterone receptors (PRA and PRB), and estrogen receptors (ER-alpha and ER-beta) in human endometrial hyperplasia.

OBJECTIVES: The effect on progesterone and estrogen receptor expression in glands and stroma after two different treatment regimens of endometrial hyperplasia was determined. METHODS: Pre- and post-treatment paraffin-embedded endometrial hyperplasia specimens from women treated with levonorgestrel (LNG) intrauterine device (n = 21) and women treated with 10 mg medroxyprogesterone acetate (MPA) for 10 days per cycle (n = 29) were examined immunohistochemically and evaluated by H-score (a semi-quantitative microscopical method evaluating staining intensity and number of stained cells, scale 0-3) for changes in expression of PRA (progesterone receptor A), PRB (progesterone receptor B), ER-alpha (estrogen receptor-alpha), ER-beta (estrogen receptor-beta) and AR (androgen receptors) after 3 months of treatment. RESULTS: All the patients in the LNG IUD group responded to treatment with no sign of hyperplasia after 3 months, while only about half of the patients given MPA orally responded. Expression of PRA, PRB, ER-alpha and ER-beta were markedly reduced after progestin treatment in both treatment groups but the reduction was much more pronounced in the LNG group (H-score for PRA was reduced from 2.61 to 0.11 in glands and from 2.26 to 0.09 in stroma in LNG group. Corresponding reduction for PRB in the LNG group was from 1.96 to 0.11 and from 0.83 to 0.01. PRA was reduced from 2.53 to 1.78 in glands and from 1.93 to 1.30 in stroma in the MPA group. Corresponding reduction for PRB in the MPA group was from 2.02 to 1.25 in glands and from 0.80 to 0.34 in stroma). Weak and focal stromal expression of AR was demonstrated in 22% of the specimens before but not after therapy. There was a statistically significant reduction in both PR and ER among the responders whereas non-responders showed no statistical change after treatment. CONCLUSION: The present study shows that LNG IUD causes an almost complete down-regulation (lack of immunohistochemical expression) of PR expression and a considerable down-regulation of ER expression in both glands and stroma. The changes in receptor expression were markedly less pronounced after treatment with intermittent oral MPA. The differences in receptor expression among responders and non-responders might serve as possible markers for therapy response.

Bcl-2, BAX, and apoptosis in endometrial hyperplasia after high dose gestagen therapy: a comparison of responses in patients treated with intrauterine levonorgestrel and systemic medroxyprogesterone.

OBJECTIVES: The aim of the study was to investigate apoptosis as a growth regulatory mechanism of gestagen in endometrial precancers and to compare differences in the apoptotic cascade after high and low dose gestagen regimens. METHOD: Pre- and post-treatment paraffin-embedded endometrial hyperplasia specimens from women treated with levonorgestrel intrauterine device (n = 26) and women treated with 10 mg medroxyprogesterone for 10 days per cycle (n = 31) were examined for changes in the expression of Bcl-2 and BAX and the extent of apoptosis after 3 months of treatment. Immunohistochemical expression in tissue specimens for Bcl-2 and BAX was evaluated by H-score. Average number of apoptotic cells per hundred cells within ten different high power field (40 x) was evaluated for each section after in situ apoptosis detection (TUNEL method). A second group of patients with endometrial hyperplasia was examined after 1 week treatment with levonorgestrel IUD (n = 6) or medroxyprogesterone (n = 5) to determine early effects on expression of Bcl-2 and BAX and the extent of apoptosis. RESULTS: All the patients in the IUD group (n = 31) but only about half of the patients in per oral group (16 of 26) responded to treatment. The glandular reduction in Bcl-2 expression was markedly greater for the IUD patients than for the patients who received oral gestagen. The decrease in BAX expression after IUD treatment was less than the reduction of Bcl-2. Decrease in glandular Bcl-2 after 3 months of treatment was coincident with a significant increase in the measurable amount of apoptosis. In stromal cells, the increase in expression of Bcl-2 and BAX was found after gestagen treatment, the response being much more marked for the IUD group. The non- responders to per oral gestagen had no Bcl-2 expression in stroma after 3 months of therapy whereas an increase was observed for the responders. After 1 week, glandular Bcl-2 expression was significantly reduced after treatment in the IUD group. As for the rest, no changes were detected in either of the groups. CONCLUSION: Our results indicate that proteins in the apoptotic cascade are regulated by gestagen therapy in human endometrial precancers. Expression of these proteins is shown to be dependent on administration form and/or type of gestagen. Stromal Bcl-2 expression appears to be a potential biomarker which can separate responders of gestagen treatment from non-responders after oral administration.